Heterocyclic sulfonamides as modulators of cardiac sarcomeres
Certain substituted sulfonamide derivatives of Formula I selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.
1. A compound represented by Formula I:
wherein:
R 1 , R 2 and the nitrogen to which they are attached form a piperazin-1-yl ring, wherein the piperazin-1-yl ring is optionally substituted with one, two or three of the following groups: alkyl, halogen, hydroxy, alkoxy, alkylenedioxy, carboxy, acyloxy, alkoxycarbonyl, aminocarbonyl, cyano, acyl, oxo, nitro, amino, sulfanyl, sulfinyl, sulfonyl, aminosulfonyl, amidino, phenyl, benzyl, heteroaryl, heterocyclyl, aryloxy, aralikoxy, heteroaryloxy, and heteroaralkoxy;
R 3 is a phenyl, isoxazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, tetrazol-5-yl, thiazolyl, thiadiazolyl or imidazolyl group, which is optionally substituted with a halogen, lower alkoxy, aryl or heteroaryl group;
R 4 is halogen;
R 5 is hydrogen, halogen, hydroxy, or lower alkyl; and
R 6 and R 7 are independently selected from hydrogen, halogen, hydroxy, and lower alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is an [1,3,4]thiadiazol-2-yl group which is optionally substituted with a phenyl group.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is 5-phenyl-[1,3,4]thiadiazol-2-yl.
4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 4 is chloro; and
R 5 , R 6 and R 7 are hydrogen.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is a 1H-imidazol-2-yl group.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein
R 4 is chioro; and
R 5 , R 6 and R 7 are hydrogen.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is oxazol-2-yl.
8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein
R 4 is chloro; and
R 5 , R 6 and R 7 are hydrogen.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 4 is chloro; and
R 5 , R 6 and R 7 are hydrogen.
10. A pharmaceutical formulation comprising a pharmaceutically accepted excipient and a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.